Alternative anticonvulsant drugs for dogs with seizure disorders

Seizure disorders represent the most frequent neurologic problem encountered in dogs. Although there are multiple causes of seizures, the most common cause is idiopathic epilepsy. About 25% to 30% of epileptic dogs have conditions that are poorly controlled despite adequate plasma concentrations of typically used anticonvulsant drugs (i.e. phenobarbital and bromide).1,2 Phenobarbital and bromide have similar adverse effects, including sedation, polyphagia, weight gain, polyuria, and polydipsia.1,2 In our experience, these side effects are often compounded when the two drugs are administered concurrently. Exacerbation of polyphagia, weight gain, polyuria, and polydipsia also occurs in dogs with seizure disorders requiring glucocorticoid therapy to control clinical signs (e.g. brain tumors, granulomatous meningoencephalomyelitis). Small-animal clinicians recognize a need for safe and effective alternatives to phenobarbital and bromide.

Numerous anticonvulsant drug options are available for people with seizure disorders. Unfortunately, most of these drugs are eliminated too rapidly when administered in dogs to be of much practical use.1,2 However, some of these alternative drugs have shown promise in dogs with seizure disorders. These drugs include clorazepate, felbamate, gabapentin, levetiracetam, and zonisamide (Table 1). For each of these drugs, published or unpublished data on the pharmacokinetics and side effects in dogs are available. Some of the information regarding their efficacy is anecdotal, based primarily on clinical experience. For most of these anticonvulsants, however, there is published information concerning efficacy in dogs with seizure disorders.

Table 1: Dosing, Costs, and Side Effects of Alternative Anticonvulsant Drugs in Dogs

The drugs discussed in this article cost considerably more than phenobarbital or bromide. Because of their increased expense, these drugs are typically used as add-on therapy to standard anticonvulsant drug regimens. In some cases, these drugs have been used as replacement therapy or as sole anticonvulsant agents. Such use of these alternative drugs is more commonly pursued with smaller dog breeds. This article provides small-animal clinicians with a reference source for alternatives to phenobarbital and bromide.

Clorazepate

Clorazepate (clorazepate dipotassium) is a benzodiazepine prodrug that acts by enhancing gamma-aminobutyric acid (GABA) activity in the brain.1-5 Clorazepate tablets are available in both regular and sustained-release formulations, but there appears to be no advantage to using the sustained-release tablets in dogs.1,6 After oral administration, clorazepate is rapidly hydrolyzed in the stomach to nordiazepam, its active metabolite. Nordiazepam subsequently undergoes hepatic metabolism. The serum elimination half-life of nordiazepam after clorazepate administration is typically four to six hours, but it may be as short as three hours in some dogs.1-5 We recommend an initial dosage of 0.5 to 1 mg/kg given every eight hours. A dosage of 2 mg/kg given every 12 hours has also been suggested.2-5 The therapeutic range in dogs receiving clorazepate is 100 to 400 ng/ml of nordiazepam.2 Because of the short and somewhat variable elimination half-life of the drug, it is important to obtain both peak and trough serum concentrations when monitoring patients. The side effects of clorazepate are similar to those of other benzodiazepine drugs (e.g. sedation, ataxia).2,3 Severe withdrawal seizures are possible if clorazepate is abruptly discontinued.7

Several potential problems are associated with clorazepate administration. With long-term use, serum nordiazepam concentrations tend to decrease with time, usually necessitating a dose increase. Although the problem is not as profound as with diazepam, long-term use of clorazepate may also lead to tolerance of its antiseizure effects. It has been demonstrated that concurrent administration of phenobarbital and clorazepate leads to marked reductions in serum nordiazepam concentrations, necessitating increased doses of clorazepate.1,2,5 Conversely, there is some evidence that simultaneous administration of clorazepate and phenobarbital can lead to increased serum phenobarbital concentrations.2 We recommend performing serum chemistry profiles every six months to monitor hepatic function in dogs receiving clorazepate, especially in those receiving phenobarbital concurrently.

No published information documents the efficacy of clorazepate in dogs with seizure disorders. In our experience, clorazepate is a moderately effective alternative anticonvulsant drug. In dogs already receiving phenobarbital, maintaining the correct dosage of clorazepate can be troublesome. Another potential use for clorazepate is for short-term treatment in dogs experiencing cluster seizure episodes.

Felbamate

Felbamate is a dicarbamate anticonvulsant drug used for both focal (partial) and generalized seizures in experimental studies in animals and clinical trials in people.1,2,8,9 Felbamate's suspected mechanisms of action include blocking N-methyl-D-aspartate (NMDA)-mediated neuronal excitation, potentiating GABA-mediated neuronal inhibition, and inhibiting voltage-sensitive neuronal sodium and calcium channels.1,2,8-11 There is also evidence that felbamate offers some protection to neurons against hypoxia and ischemic damage.8,9 About 70% of oral felbamate in dogs is excreted in the urine unchanged; the remainder undergoes hepatic metabolism. The half-life of felbamate in adult dogs is about five to six hours, with a range of four to eight hours.1,2,8,11,12 Although felbamate is well-absorbed after oral administration in adult dogs, it has been shown that the bioavailability in puppies may be only 30% of that in adults. The half-life in puppies has also been demonstrated to be much shorter than in adult dogs (i.e. about 2.5 hours).13,14

In adult dogs, we recommend an initial felbamate dosage of 15 mg/kg given every eight hours. Felbamate has a wide margin of safety in dogs, with serious toxic effects usually not apparent when dogs are given less than 300 mg/kg/day.1,2,8,10,15 If the initial dose of felbamate is ineffective, we generally increase it in 15-mg/kg increments every two weeks until efficacy is achieved, unacceptable side effects become evident, or the drug becomes cost-prohibitive. The therapeutic range for serum felbamate concentrations in dogs is thought to be similar to that in people (20 to 100 µg/ml).2,10 Serum felbamate assays are typically costly and are usually unnecessary because of the drug's low potential for toxicity.

Side effects are infrequent with felbamate use in dogs. A principal advantage of felbamate over standard anticonvulsant drugs is that it does not cause sedation. Because felbamate undergoes some hepatic metabolism, liver dysfunction is a potential side effect.1,2,8,10 In one study, four of 12 dogs receiving felbamate as an add-on therapy developed liver disease. However, all of these dogs were also receiving high doses of phenobarbital.16 In people, felbamate has been shown to increase serum phenobarbital concentrations in some patients receiving combination therapy.2,17 It is unclear whether felbamate, phenobarbital, or a combination of the two drugs is responsible for the reported hepatotoxicity in dogs. In people, serious hepatotoxicity is rarely encountered with felbamate use and almost always occurs in patients receiving other anticonvulsant drugs concurrently.2,9,18 If a dog already has a liver problem, felbamate should be avoided. In our experience, if a dog develops liver disease, the condition is typically reversible when felbamate is discontinued. However, we rarely encounter dogs with liver problems in which felbamate has been used as the sole therapy.

Aplastic anemia from bone marrow suppression has been reported in people receiving felbamate at a rate of 10 per 100,000 patients; this uncommon side effect is also usually encountered in patients receiving combination anticonvulsant drug therapy.2,18 This devastating side effect does not appear to occur in dogs receiving the drug. In one report, however, reversible bone marrow suppression was suspected in two dogs receiving felbamate; one dog developed mild thrombocytopenia, the other mild leukopenia.19 Both of these abnormalities resolved with felbamate discontinuation. One patient in this report developed bilateral keratoconjunctivitis sicca; it is unknown if this was related to felbamate use.19 Generalized tremor activity in small-breed dogs receiving high doses of felbamate has also been reported as a rare side effect.10

The limited published material on felbamate's efficacy mirrors our clinical experience. In one report of refractory epileptic dogs, 12 of 16 patients had reduced seizure frequency after felbamate therapy was initiated.16 In another report of six dogs with suspected focal seizure activity, all six dogs experienced a substantial reduction in seizure frequency when felbamate was used as a sole anticonvulsant drug; two of these dogs became seizure-free.19

We have used felbamate extensively to treat dogs with seizure disorders. In our experience, felbamate is effective both as an add-on therapy and as a sole anticonvulsant agent in patients with focal and generalized seizures. Because felbamate does not have a sedative effect, we have found it particularly useful as a monotherapy in dogs exhibiting obtunded mental status from their underlying neurologic disease (e.g. brain tumor, cerebral infarct). We have found side effects from felbamate to be infrequent. However, because of the potential for hepatotoxicity, serum chemistry profiles should be preformed every six months in dogs receiving felbamate, especially if they are receiving phenobarbital concurrently. It would also be prudent to perform complete blood counts every few months, in the unlikely event that a blood dyscrasia develops.

Gabapentin

Gabapentin is a structural analogue of GABA. Gabapentin appears to exert its antiseizure effects by enhancing the release and action of GABA in the brain and inhibiting neuronal sodium channels.1,2,8,10,17,18 Gabapentin is well-absorbed in both dogs and people, with peak serum concentrations occurring within one to three hours after administration. In people, absorption is somewhat dose-dependent, relying on a saturable amino acid transport mechanism in the gastrointestinal tract. This saturable transport process has been theorized as the reason anticonvulsant effects may last longer than expected based on the serum half-life of the drug.2,17

In people, virtually all of the drug is excreted unchanged in the urine (i.e. no hepatic metabolism). In dogs, however, 30% to 40% of the oral dose undergoes hepatic metabolism to N-methyl-gabapentin.1,2,8,10,20,21 Even though gabapentin undergoes some hepatic metabolism, there is no appreciable induction of hepatic microsomal enzymes in dogs. Gabapentin's half-life in dogs is three or four hours. The recommended dosage in dogs is 25 to 60 mg/kg divided every six to eight hours.1,2,10,20,21 We recommend an initial dosage of 10 mg/kg given every eight hours. The suspected serum therapeutic range in dogs is 4 to 16 mg/L.18 As with felbamate, serum gabapentin concentrations are rarely obtained in dogs.

Although long-term toxicity trials in dogs have not been reported, gabapentin seems to be well-tolerated, usually with no sedation or other side effects. There are no clinical reports on the efficacy of gabapentin in dogs with seizure disorders. In our experience, gabapentin is only occasionally useful in dogs. In people, gabapentin appears to be much more effective in treating focal rather than generalized seizure disorders.18 Because of its short half-life in dogs, gabapentin should be administered at least every eight hours, and possibly every six hours, to maintain serum gabapentin concentrations within the therapeutic range. The potential need for giving the drug every six hours can make it difficult for some pet owners to reliably administer gabapentin.

Levetiracetam

Levetiracetam is a new anticonvulsant drug for treating focal and generalized seizure disorders in people and has been studied in several experimental animal models.1,17,18,22-26 The mechanism of action for levetiracetam's anticonvulsant effects is unknown. Unlike other anticonvulsant drugs, levetiracetam does not appear to directly affect common neurotransmitter pathways (e.g. GABA, NMDA) or ion channels (e.g. sodium, T-type calcium).17,22-24 There is some evidence that levetiracetam may inhibit high-voltage-activated neuronal calcium currents. Levetiracetam may also act by interfering with negative allosteric modulators of inhibitory GABA and glycine pathways in the brain.23,24

Orally administered levetiracetam approaches 100% bioavailability in dogs, with a serum half-life of three or four hours (UCB Pharma, Inc.: Unpublished data, 2004).27 Levetiracetam appears to exert an anticonvulsant effect that persists longer than its presence in the bloodstream would suggest.23 About 70% of oral levetiracetam is excreted unchanged in the urine; the remainder of the drug is hydrolyzed in the serum and other organs. There does not appear to be any hepatic metabolism of levetiracetam in people or dogs (UCB Pharma, Inc.: Unpublished data, 2004).22-24,27 The effective serum concentration is 5 to 45 µg/ml in people.18 Since there is no clear relationship between serum drug concentration and efficacy for levetiracetam, and since the drug has an extremely high margin of safety, routine therapeutic drug monitoring is not typically recommended in people.17,23,25,26 Based on limited pharmacokinetic information in dogs, we recommend an initial dosage of 20 mg/kg given every eight hours (UCB Pharma, Inc.: Unpublished data, 2004).27 This dose can be increased by 20-mg/kg increments until efficacy is achieved, side effects become apparent, or the cost becomes prohibitive.

Long-term toxicity data for levetiracetam in dogs confirm that the drug is extremely safe. In one study, dogs were administered oral levetiracetam at dosages up to 1,200 mg/kg/day for one year.28 One of eight dogs receiving 300 mg/kg/day developed a stiff, unsteady gait. The remainder of side effects (salivation, vomiting) were limited to the dogs receiving 1,200 mg/kg/day. There were no treatment-related mortalities and no treatment-related histopathologic abnormalities (UCB Pharma, Inc.: Unpublished data, 2004). We have used levetiracetam in dogs as an add-on therapy with favorable results. In a recent report, using levetiracetam as an add-on drug in 15 epileptic dogs was associated with a significant reduction (54%) in seizure frequency, with no apparent side effects.28

Zonisamide

A sulfonamide-based anticonvulsant recently approved for use in people, zonisamide is effective in treating focal and generalized seizures with minimal side effects.29-33 Suspected anticonvulsant mechanisms of action include blocking T-type calcium and voltage-gated sodium channels in the brain, modulating dopaminergic metabolism in the central nervous system, scavenging free radical species, enhancing actions of GABA in the brain, and inhibiting carbonic anhydrase activity.17,18,29-31 Zonisamide is metabolized primarily by hepatic microsomal enzymes, and the half-life in dogs is about 15 hours.34 In people, the half-life of zonisamide is dramatically shorter (up to 50%) in patients concurrently receiving drugs that stimulate hepatic microsomal enzymes.33,35 A similar phenomenon may also occur in dogs, although this is not well-documented.

When zonisamide is used as an add-on therapy for dogs already receiving drugs requiring hepatic metabolism (e.g. phenobarbital), we recommend an initial oral dosage of 10 mg/kg given every 12 hours. This dosage has been shown to maintain canine serum zonisamide concentrations within the therapeutic range reported in people (10 to 40 µg/ml) when used as an add-on therapy.18,36 For dogs not receiving hepatic microsomal enzyme-inducing drugs, we recommend 5 mg/kg given every 12 hours. Trough serum zonisamide concentrations should be checked about one week after you institute therapy. Zonisamide has a high margin of safety in dogs. In one study, minimal side effects occurred in beagles administered zonisamide dosages up to 75 mg/kg/day for one year.37

In a recent study, zonisamide decreased seizure frequency by at least 50% in seven of 12 dogs with refractory idiopathic epilepsy. In this responder group, the mean reduction in seizure frequency was 81.3%. In six of the seven responder dogs, phenobarbital was able to be reduced by an average of 92.2%. Mild side effects (e.g. transient sedation, ataxia, vomiting) occurred in six dogs (50%); none of the side effects were considered severe enough to discontinue zonisamide therapy.36

We have used zonisamide as a sole anticonvulsant drug in a number of dogs, primarily small-breed dogs whose owners wanted to avoid the side effects characteristic of phenobarbital and bromide. Our impression is that zonisamide is usually effective as a sole anticonvulsant therapy, with few to no apparent side effects.

Miscellaneous anticonvulsant drugs

Several relatively new anticonvulsants used for seizure disorders in people have been suggested as potential alternatives in dogs. These drugs include lamotrigine, oxcarbazepine, tiagabine, and topiramate. Information about using these drugs in dogs with seizure disorders is limited to nonexistent. However, given the drugs' short half-lives in dogs and their expense, they will probably not prove useful in dogs. In addition to having a half-life in dogs of only two or three hours, lamotrigine undergoes significant hepatic metabolism in this species to a potentially cardiotoxic compound.10 Oxcarbazepine is thought to induce its own hepatic metabolism in dogs and has been demonstrated to have only a one-hour half-life after eight days of repeated oral dosing.38 Tiagabine has a half-life of about two hours in dogs and causes marked sedation and visual impairment in dogs at relatively low doses.39 The half-life of topiramate in dogs is only two to four hours.40

Curtis W. Dewey, DVM, MS, DACVIM (neurology), DACVS

Georgina Barone, DVM, DACVIM (neurology)

Kerry Smith, DVM

Department of Neurology and Neurosurgery

Long Island Veterinary Specialists

163 S. Service Road

Plainview, NY 11803

Gregg D. Kortz, DVM, DACVIM (neurology)

California Veterinary Neurology and Neurosurgery Specialists

1100 Atlantic St.

Roseville, CA 95678

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